HSCT, is it remission, or is it a cure for MS?

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Most of you who read the blog know that I’m highly cynical when it comes to the word ‘CURE’ in the same sentence as a brain disorder or autoimmunity. In fact, it’s very similar to hearing the word VEGAN in the same sentence as pizza or donuts (apologies to any vegans who are currently sitting across from one of these right now; there’s always tomorrow).

Why?

Where do I begin?….

Science is imperfect, with perfect people searching for imperfect outcomes (an oxymoron if ever there was one), we live on Earth (the only planet in our solar system not named after a mythical being, but deriving its name from Anglo-Saxon erda meaning ground or soil, so some realism is needed here), and we are but small ants in the bigger schemes of things etc., etc.

But, may be from time to time the Universe my yet throw us a bone, or more likely we simply stumble across the answer just by chance alone. Over this decade, in the space of just a few years, we have seen the greatest development in targeted gene therapies that science has to offer, and for the first time since their characterization, we have the hope of curing some of the world’s rarest and incurable genetic disorders.

So, why can’t MS have its moment in the limelight? In my opinion, HSCT (Hematopoietic Stem Cell Transplantation) currently offers the best opportunity of achieving this goal.

What should be the aims of HSCT treatment?

At worst, remission. At best, a cure.

Remission is when your clinical examination and MRI scans indicate that the MS is no longer active, i.e. “no evidence of disease activity” (NEDA). A cure, on the other hand, is when the immune system stops targeting your nervous system, i.e. there is no longer CNS-directed autoimmunity. How, you’d judge the latter is open to debate, but the authors in this publication (see below) feel that the disappearance of oligoclonal bands (antibody synthesis) in the cerebrospinal fluid (CSF) is a good indicator of this. They have also included into this definition stabilization of CSF neurofilament levels into this (i.e. no further ongoing neuronal injury).

This is a very, very small study (n=10), and the protocol is not the partial immunoblation that is now being used in the UK, but full clearance of the bone marrow using proper-chemotherapy (BEAM/ATG) mainly (although one person did have the low intensity cyclophosphamide/ATG conditioning regimen). Two out of the ten went onto have a clinical relapse, and were started on Copaxone (I note, with interest that the choice by the treating physicians was to go with a low-efficacy agent; possibly to reduce the future occurrence of PML (progressive multifocal leukoencephalopathy), which is more likely if a higher efficacy agent was used). But, overall 50% achieved remission, and 30% a cure (see Figure 1 below). I might add, that alemtuzumab achieved ~68% remission at the same time point, but we’re not comparing like with like here.

Figure 1: MS remission/cure in the individuals treated with HSCT

Of course, HSCT is not without adverse events, and some of the side effects described in the study would be considered serious in nature (see Figure 2 below).

Figure 2: Adverse events according to Common Toxicity Criteria

But, if you are in that lucky 30% that achieve a cure with this treatment, then who am I to argue with the facts?

ABSTRACT

Acta Neurol Scand. 2019 Jul 12. doi: 10.1111/ane.13147. [Epub ahead of print]
Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation.
Tolf A, Fagius J, Carlson K, Åkerfeldt T, Granberg T, Larsson EM, Burman J.

OBJECTIVES:

To determine if treatment with autologous hematopoietic stem cell transplantation can induce sustained complete remission in patients with multiple sclerosis (MS).

MATERIAL AND METHODS:

Case series of patients with relapsing-remitting MS (n=10) treated at a single center between 2004 and 2007 and followed up for 10 years. The patients were treated with a BEAM/ATG conditioning regimen (n=9) or a cyclophosphamide/ATG conditioning regimen (n=1) followed by infusion of unmanipulated autologous hematopoietic stem cells. The primary endpoint was sustained complete remission. Sustained complete remission was defined as ‘no evidence of disease activity-4’, sustained for a period of at least 5 years without any ongoing disease-modifying treatment. Furthermore, MS was considered as ‘resolved’ if intrathecal IgG production and cerebrospinal fluid neurofilament light levels were normalized as well.

RESULTS:

Five out of 10 patients were in sustained complete remission at the end of the study. In 3 of them, MS was resolved.

CONCLUSIONS:

Our data demonstrate that sustained complete remission after autologous hematopoietic stem cell transplantation for MS is possible.

About the author

Neuro Doc Gnanapavan

16 comments

  • Don’t you think we could have a cure o NEDA with Cladribine and keeping special care of vitamin D? I think a HSCT is too risky and maybe a good DMT could give the same results if the immunological environment is adequate.

    • NEDA-3 i.e. excluding evidence of an impact on brain volume loss for the heavy hitters is Natalizumab at 2y was 44.4%, cladribine at 4y 47%, alemtuzumab at 3y 45%. Ocrelizumab oddly they rebaselined their MRI and 80% NEDA-3 at 6-24months, but interestingly IFN-b (Rebif) was 57! I don’t think Rebif has suddenly become the best drug option, but it’s more likely that the trial population for the study were not as severe…

  • Monitoring NFL and OCB levels in CSF is common practise in Uppsala Sweden after HSCT. I was treated in Uppsala 3 years ago by Dr Burman and my levels also returned to normal. I expect more data on this will follow as many more than 10 patients have been treated in Uppsala. They are probably waiting on the long term results before they can publish. Hopefully I will reach the 5 year mark of NEDA and normalised NFL and OCB levels as well, especially since I was treated with the non-myelo MIST protocol for which long term data still is lacking.

  • “Science is imperfect, with perfect people searching for imperfect outcomes (an oxymoron if ever there was one), we live on Earth (the only planet in our solar system not named after a mythical being, but deriving its name from Anglo-Saxon erda meaning ground or soil, so some realism is needed here), and we are but small ants in the bigger schemes of things”.

    That is poetry!

    Unsure about the patient’s who needed further treatment going on such “mild” agents, but one wonders if considering those said patients also seemed to have an improvement in their CCA, NFL and otherwise dulling down of disease activity(at least in a relative sense), the treatment changed their disease to a milder form of the disease?

    • Thanks!

      Not certain about CCA. NFL does seem to improve, but for how long is the question. This is always what people talk about when they reference HSCT, which is re-booting the immune system.

  • “The estimated annual callosal atrophy rate before treatment was 10%, which is about 8 times higher than expected in randomly selected MS patients31 and reflects the characteristics of the patients in this cohort, with unusually aggressive disease. Previous investigators have demonstrated a continuous and even accelerated brain atrophy directly following HSCT.10, 35, 36 Similarly, we found that in an initial phase, atrophy continued almost unimpededly after HSCT. In one recent study, the atrophy rate reached normal levels 2.5 years after HSCT36, and for this reason we postulated a change in atrophy rate at this time point in our statistical model. From 2.5 years after HSCT to the end of follow-up, continuous callosal atrophy was virtually non-existent in 8/10 patients, which suggests that the degenerative process was halted by the therapeutic intervention. Two patients exhibited a modest callosal atrophy rate after this time point, which may be explained by extensive damage to the brain and Wallerian degeneration persisting for some time beyond 2.5 years.”

  • I cannot understand why people are using “partial ablation” instead of BEAM+ATG. What’s the point?
    We have alemz for that, why theyr regiment should be any better

      • ” My post HSCT hematologist Dr. who knows EVERYTHING about everything dealing with HSCT says that they have been saying for years that HSCT should be a frontline treatment because their perspective coming from cancer treatment is hit it with the biggest drug you have and kill the disease. Neurologist’s perspective is do the lease impactful thing possible to avoid doing any harm.”

    • Also, busulfan is neurotoxic. And when the outcomes are comparable without the added risks why would one use BEAM?

  • “I might add, that alemtuzumab achieved ~68% remission at the same time point, but we’re not comparing like with like here.” – What is meant by this statement?

  • How do you know that MS was cured? How much time elapsed after treatment before this statement was made? Isn’t it possible that they were just in remission and the disease might come back again in the future? Where does the certainty that disease is now gone come from?

  • Maybe we should not count much on OCBs to verify a cure for MS. OCBs can be absent in a lot of MS patients, can be present in non MS patients, can vanish with DMTs that are inferior to HSCT, can persist in otherwise normal MRI (including brain atrophy) HSCT MS patients. We dont know what they do and why they are present, so they should be investigated but not be a part of the cure criteria for now.
    NFl levels, absolutely.

  • (Stolen it)
    From Joachim Burman’s PhD thesis out of Uppsala …”intrathecal antibody production can be demonstrated in a vast majority of MS patients. It has been claimed that
    oligoclonal IgG bands persist in the CSF of almost all patients, but in another study with a high intensity regimen 75% retained oligoclonal bands.143 In Swedish patients, only 69 % retained oligoclonal bands after a
    low-intermediate conditioning. This discrepancy may be due to that Swedish
    patients were on average treated earlier, most of them still in the relapsing remitting phase. The biological significance of these antibodies is not clear and for all we know they could be an epiphenomenon. It is well known that
    oligoclonal bands are present to variable degrees in other inflammatory CNS
    disease, not least in infection with B burgdorferi, when antibody
    production can persist for years after the infection has been cleared.

    The latter illustrates that is not necessary to lose the oligoclonal bands to
    allow us to speak of cure”…

    https://www.diva-portal.org/smash/get/diva2:714003/FULLTEXT01.pdf

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